DESCRIPTION: The applicant notes that identification of high affinity and specific ligands to receptors and enzymes is one of the major goals of chemical and biological research. The identification of such ligands is a fundamental step in the development of molecular probes for the study of receptor and enzyme function, as well as for the eventual development of therapeutic agents. The design, synthesis, and evaluation of compound libraries has had a profound impact on these efforts. Peptide and oligonucleotide libraries were the focus of early work in the area. While these studies clearly demonstrated the power of library synthesis and screening strategies, peptides and oligonucleotides generally have poor oral activities and rapid in vivo clearing times, and therefore their utility as pharmacological probes or therapeutic agents is often limited. In the initial grant the applicant proposed that libraries of small molecules with useful pharmacokinetic properties could also be used to identify high affinity ligands to receptors and enzymes. Over the past 4 years, small molecule library synthesis and screening efforts have expanded extremely rapidly in academic and industrial research. However, significant improvements still should be made in order for the full power of library strategies to be realized. In particular, regardless of whether libraries are prepared on solid support or in solution, more sophisticated chemistry that provides general access to more complex structures must be developed. This is most important for optimizing lead compounds that are of modest potency in order to achieve the level of affinity and specificity that is required for therapeutics and for molecular probes to study biological function. Accordingly, the applicant will address the following specific aims. (1) Expand upon the chemistry that we have developed towards benzodiazepine libraries with an emphasis towards the optimization of benzodiazepine leads that have been identified towards therapeutically relevant targets. (2) Expand upon the complexity of molecules that can be accessed in a library format. The work will in particular focus on prostaglandins, for which both the natural and unnatural derivatives modulate wide spectrum of physiological activities. These molecules present a challenge in synthesis due to their delicate and complex structures and will serve to test the limits of combinatorial approaches. (3) Demonstrate the utility of the developed chemistry by identifying small molecule probes to study the structure, function, or potential therapeutic relevance of important biological receptors.